Method for preparation of pitavastatin and pharmaceutical acceptable salts thereof

ABSTRACT

The present invention discloses a compound, which is alkali or alkaline earth metal salts of pitavastatin, wherein the alkali or earth metal comprise one or more of magnesium, zinc, potassium, strontium and barium.

FIELD OF THE INVENTION

The present invention relates to processes for the preparation ofpitavastatin and pharmaceutically acceptable salts thereof. Inparticular, the present invention provides processes for the preparationof pitavastatinalkali or alkaline earth metal salts in crystalline andamorphous forms.

BACKGROUND OF THE INVENTION

Pitavastatin calcium is chemically known as(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoicacid calcium salt having the formula IA is known in the literature.

Pitavastatin is a synthetic lipid-lowering agent that acts as aninhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) reductase(HMG-CoA Reductase inhibitor). This enzyme catalyzes the conversions ofHMG-CoA to mevalonate, inhibitors are commonly referred to as “statins”.Statins are therapeutically effective drugs used for reducing lowdensity lipoprotein (LDL) particle concentration in the blood stream ofpatients at risk for cardiovascular disease. Pitavastatin is used in thetreatment of hyperchloesterolemia and mixed dyslipidemia.

Pitavastatin calcium has recently been developed as a new chemicallysynthesized and powerful statin by Kowa Company Ltd, Japan. On the basisof reported data, the potency of Pitavastatin is dose-dependent andappears to be equivalent to that of Atorvastatin. This new statin issafe and well tolerated in the treatment of patients withhypercholesterolaemia. Significant interactions with a number of othercommonly used drugs can be considered to be extremely low.

Processes for the preparation of Pitavastatin are described inEP-A-0304063 and EP-A-1099694 and in the publications by N. Miyachi etal. in Tetrahedron Letters (1993) vol. 34, pages 8267-8270 and by K.Takahashi et al. in Bull. Chem. Soc. Japan (1995) Vol. 68, 2649-2656.These publications describe the synthesis of Pitavastatin in greatdetail but do not describe the hemi-calcium salt of Pitavastatin. Thepublications by LA. Sorbera et al. in Drugs of the Future (1998) vol.23, pages 847-859 and by M. Suzuki at al. in Bioorganic & MedicinalChemistry Letters (1999) vol. 9, pages 2977-2982 describe Pitavastatincalcium, however, a precise procedure for its preparation is not given.A full synthetic procedure for the preparation of Pitavastatin calciumis described in EP-A-0520406. In the process described in this patentPitavastatin calcium is obtained by precipitation from an aqueoussolution as a white crystalline material with a melting point of190-192° C.

US20090182008 A1 discloses polymorphic form A, B, C, D, E, and F, andthe amorphous form of Pitavastatin Calcium salt (2:1). In particular,crystalline Form A having water content from about 5% to about 15% andprocess for its preparation are disclosed.

US20090176987 A1 also discloses polymorphic form crystal form A ofPitavastatin Calcium which contains from 5 to 15% of water and whichshows, in its X-ray powder diffraction as measured by using CuKαradiation, a peak having a relative intensity of more than 25% at adiffraction angle (2θ) of 30.16°.

WO2007/132482 A1 discloses a novel process for the preparation ofPitavastatin Calcium by condensing bromide salt of formula-3 withaldehyde compound of formula-4 to obtain olefinic compound of formula-5and converting olefinic compound to Pitavastatin Calcium via organicamine salt for purification.

There are no reports available in the prior art for the preparation ofPitavastatin Magnesium. Thus, the inventors of the present inventionsprovide a novel pharmaceutically acceptable salt of Pitavastatin,preferably magnesium salt.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided alkali oralkaline earth salt of quinoline derivatives such as pitavastatin, aHMG-CoA inhibitors, more specially, the present invention provides anovel process for the preparation of pitavastatinmagnesium it iscrystalline and amorphous form.

In one embodiment, there is provided a novel process for the preparationof pitavastatin and its pharmaceutically acceptable salts. Inparticular, pitavastatinalkali or alkaline earth metal comprises one ormore of magnesium, zinc, potassium, strontium, barium and the like.Pitavastatin, which is chemically known as(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoicacid and its pharmaceutically acceptable salts having the generalformula I

wherein, M is K⁺, Mg⁺², Sr⁺², Zn⁺², Ba⁺².

In one preferred embodiment, there is provided a novel process for thepreparation of pitavastatin and its pharmaceutically acceptable salts,particularly pitavastatinmagnesium which is chemically known as(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoicacid Magnesium salt having the formula IB.

In second embodiment, there is provided a novel salt,pitavastatinmagnesium of Formula (IB)

In yet another embodiment, there is provided pitavastatinmagnesium itits crystalline form having X-ray powder diffraction peaks at 10.1,13.2, 19.3 and 27.2±0.2 (2θ).

In further embodiment, there is provided a process for the preparationof pitavastatinmagnesium of formula (1B), the process comprising:

(a) reacting phosphonium bromide compound of Formula-IV with an aldehydecompound of Formula-III in the presence of an alkali or alkaline earthmetal base in one or more suitable polar aprotic solvent to provide(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester compound of formula-II;(b) hydrolyzing the compound of Formula-II under the acidic conditionsto remove the acetonide protection to form a diol compound;(c) treating the diol compound of step (b) in-situ with an alkali metalhydroxide to form the corresponding alkali metal salt of pitavastatin(I);(d) treating alkali metal salt of pitavastatin with a magnesium sourceto obtain pitavastatinmagnesium; and(e) isolating the pitavastatinmagnesium.

According to the embodiments, the process for the preparation ofpitavastatinmagnesium according to the present inventions providescrystalline form of pitavastatinmagnesium having water content in therange of from about 7% to about 12% wt/wt.

According to another embodiment, the compound(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester of formula (II) in crystalline form.

According to another embodiment, there is provided an improved processfor the purification of(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester of formula (II) to obtain in crystalline form.

According to the further embodiments, there is provided a process forthe preparation of pitavastatinmagnesium in amorphous form, the processcomprising:

(a) providing a solution comprising pitavastatinmagnesium in a suitableorganic solvent wherein the organic solvent is one or more of achlorinated solvent, alcoholic solvent, ketonic solvent, aliphatic orcyclic ether and mixtures thereof;

(b) adding suitable antisolvent to the solution; and

(c) recovering the amorphous form of the pitavastatinmagnesium.

According to the further embodiments, there is provided a process forthe preparation of an amorphous form of the pitavastatinmagnesium havingwater content less than about 2% wt/wt,

the process comprising:

(a) providing pitavastatinmagnesium in crystalline form having watercontent in the range of about 8% to about 12% wt/wt;

(b) contacting the pitavastatinmagnesium with humid air in a fluidizedbed drier, or maintaining the pitavastatinmagnesium at a temperature offrom about 5 to about 60° C., under pressure of less than 30 mm/Hg for aperiod of from about 1 to 5 days; and

(c) recovering the pitavastatinmagnesium in the amorphous form havingwater content less than about 2% wt/wt.

According to the further embodiment, there is provided substantiallypure pitavastatinmagnesium in stable crystalline form.

DETAILED DESCRIPTION OF DRAWINGS

FIG. 1: X-ray diffraction pattern of crystalline pitavastatinmagnesiumhaving about 8% to about 12% water content prepared as per the processof Example-2

FIG. 2: X-ray diffraction pattern of amorphous pitavastatinmagnesiumprepared as per the process of Example-3

FIG. 3: X-ray diffraction pattern of crystalline(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester compound (II).

FIG. 4. DSC thermogram of crystalline(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester compound (II) having endothermic peak at about116.04° C.

The details of one or more embodiments of the inventions are set forthin the description below.

Other features, objects and advantages of the inventions will beapparent from the description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The prior art discloses the use of organic amine salts of Pitavastatinfor obtaining better purity. The present inventors have found thatpitavastatinalkali or alkaline earth metal salt prepared by using theprocess provided herein provides better yield and purity and avoids theuse of amine salt formation. This significantly improves the processeconomics and commercial viability.

As used here in the term “isolation” may include filtration, filtrationunder vacuum, centrifugation, and decantation. The product obtained maybe further or additionally dried to achieve the desired moisture values.For example, the product may be dried in a tray drier, dried undervacuum and/or in a Fluid Bed Drier.

Optionally, the solution, prior to any solids formation, can be filteredto remove any undissolved solids, solid impurities and the like prior toremoval of the solvent. Any filtration system and filtration techniquesknown in the art can be used.

The term “Suitable organic solvent” means a single or a combination oftwo or more solvents.

The term “Substantially pure” means pitavastatinalkali or alkaline earthmetal prepared by the process of the present invention is substantiallyfree from any single individual impurities like desfluoro impurity,cis-isomer impurity, Pitavastatin 5-oxo impurity, pitavastatinlactoneimpurity, pitavastatin t-butyl diol ester impurity, andpitavastatincondensed impurity.

Further the term “substantially pure” means pitavastatinalkali oralkaline earth having purity greater than 99%. In particular, it may begreater than 99.5% by area percentage of HPLC. In particular, containingless than about 0.1% of single individual impurity as herein describedabove and total impurities not more than 1.0% by area percentage ofHPLC.

Particularly, pitavastatindiastereomeric impurity andpitavastatinenantiomeric impurity are present less than about 0.3% byarea percentage of HPLC.

The above impurities are present in the preparation ofpitavastatinalkali or alkaline earth metal salts includes the followingwhich were determined from an HPLC analysis of different batches ofpitavastatinalkali or alkaline earth metal salts produced by the methoddescribed in the specification herein after:

In first embodiment, there is provided alkali or alkaline earth metalsalts of pitavastatin, wherein the alkali or alkaline earth metalcomprises one or more of magnesium, zinc, potassium, strontium, bariumand the like. In particular, it may comprises one or more of magnesium,zinc and potassium.

In second embodiment of the present invention, there is provided a novelsalt pitavastatin magnesium of Formula (IB)

In particular, the pitavastatin magnesium may be a hydrate having watercontent in the range of from about 7% to about 12% wt/wt. In particular,the water content may be about 9% to about 12% wt/wt. More particularly,the water content may be about 10% to about 12% wt/wt as measured by theknown techniques in the art like Karl-Fisher method.

In yet another embodiment, there is provided pitavastatin magnesium incrystalline form having x-ray powder diffraction peaks at 10.1, 13.2,19.3 and 27.2±0.2 (2θ). In particular, the pitavastatin magnesiumcrystalline form is having an x-ray powder diffraction pattern as shownin FIG. 1. Further embodiment includes pitavastatin magnesium havingoptical rotation of about +22.0 to +22.5 in 1% DMSO at 20±0.5° C.

In yet another embodiment, there is provided an amorphous form of thepitavastatin magnesium having x-ray powder diffraction peaks as shown inFIG. 2.

According to further embodiment, the amorphous form of pitavastatinmagnesium is having the water content less than about 5% wt/wt. Inparticular, it may have the water content less than about 2% wt/wt.

In a third embodiment, there is provided a process for the preparationof pitavastatin and its pharmaceutically acceptable salts, inparticularpitavastatin alkali or alkaline earth metal comprises one ormore of magnesium, potassium, zinc and the like.

The pitavastatinalkali metal salts is chemically known as(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoicacid salt having the general Formula (I)

wherein, M is Na⁺, K⁺, Li⁺.

In a further embodiment of the present invention, there is provided apitavastatinzinc of Formula (IC)

In yet another aspect of the present invention, there is provided apitavastatinpotassium of formula (ID)

According to a further embodiment, there is provided a process for thepreparation of pitavastatinmagnesium of formula (1B),

the process comprising:(a) reacting phosphonium bromide compound of Formula-IV

with an aldehyde compound of Formula-III

in the presence of an alkali or alkaline earth metal base in one or moresuitable polar aprotic solvent to provide(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester compound of formula-II,

(b) hydrolyzing the compound of Formula-II under the acidic conditionsto remove acetonide protection to form diol compound;(c) treating the diol compound of step (b) in-situ with an alkali metalhydroxide to form the corresponding alkali metal salt of Pitavastatin(I);

wherein, M is Na⁺, K⁺, Li⁺;(d) treating the alkali metal salt of pitavastatin (I) with a magnesiumsource to obtain pitavastatinmagnesium; and(e) isolating the pitavastatin magnesium.

The phosphonium bromide compound of Formula-IV and aldehyde compound ofFormula-III can be reacted in the presence of alkali or alkaline earthmetal bases. The alkali or alkaline earth metal bases comprises one ormore of sodium hydroxide, potassium hydroxide, lithium hydroxide,potassium carbonate, sodium carbonate, lithium carbonate, cesiumcarbonate and the like. In particular, it may be potassium carbonate.

Embodiments includes that the reaction may be performed in a suitablepolar aprotic solvent comprises one or more dimethylformamide,dimethylsulfoxide, dimethylacetamide, tetrahydrofuran,N-methylpyrrolidone or mixtures thereof. In particular, it may bedimethylsulfoxide. The reaction may be performed at an ambienttemperature i.e. at about 15° C. to about 40° C. In particular, it maybe from about 20° C. to about 35° C.

The reaction mixture may be stirred for about 5 to 15 hours tillcompletion of the reaction, in particular for 10 hours. The reactionmixture may be further treated with suitable organic solvents liketoluene, xylene, methylene dichloride, ethyl acetate for extracting thecompound of Formula-II. Particularly, the compound of Formula-II isextracted by using toluene.

In general, the compound of Formula-II may be isolated by removal oftoluene followed by addition of isopropanol. After the addition ofisopropanol, the reaction mixture can be heated to 40° C. to 80° C.,preferably 60° C. to 70° C. and cooling to 15° C. to obtain olefincompound of Formula (II). The compound of Formula (II) may optionally bepurified in suitable polar solvent like methanol, ethanol, Isopropanol,acetone, DMF, ethyl acetate, butyl acetate and the like. In particular,the compound of Formula (II) may be purified using methanol.

Further embodiments of the process include, hydrolysis of compound ofFormula (II). The hydrolysis of olefin compound is done under the acidicconditions to remove the acetonide protection and to form diol compound.The suitable acids comprise one or more of hydrochloric acid, aceticacid, sulfuric acid, nitric acid, phosphoric acid and the like. Inparticular it may be hydrochloric acid.

The diol compound obtained is in-situ treated with an alkali metalhydroxide selected from sodium hydroxide, potassium hydroxide, lithiumhydroxide and the like.

In particular it may be sodium hydroxide to obtain corresponding alkalimetal salt of pitavastatin (I)

herein M is Na⁺.

Embodiments of the process includes treating alkali metal salt offormula (I) of pitavastatin, in particular it may be pitavastatinsodiumwith magnesium source. Preferred magnesium source comprises one or moreof magnesium chloride, magnesium methoxide, magnesium acetate andhydrates thereof. In particular, it may be magnesium chloridehexahydrate.

In general, the pitavastatinmagnesium prepared by the method asdescribed above, can be dried in hot air oven at 40° C. to 45° C. for atleast about 4 to 24 hours having water content in the range of about 8%to 12% wt/wt to obtain pitavastatinmagnesium in crystalline form.

Embodiments further includes, drying pitavastatin magnesium having watercontent in the range of about 8% to about 12% wt/wt for about 8 hours ormore; in particular, for at least about 24 hours so as obtainsubstantially anhydrous pitavastatin magnesium having water content lessthan about 2% wt/wt.

According to the preferred embodiment, there is provided an improvedprocess for the preparation of(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester of Formula (II),

the process comprising:(a) reacting phosphonium bromide compound of Formula-IV with an aldehydecompound of Formula-III in the presence of an alkali or alkaline earthmetal base in one or more suitable polar aprotic solvent to provide(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester compound of Formula-II,(b) treating compound of Formula-II with one or more suitable polarsolvent to form reaction mixture;(c) heating the reaction mixture at an elevated temperature;(d) cooling the reaction mixture to ambient temperature; and(e) isolating the(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester in crystalline form.

The phosphonium bromide compound of Formula-IV and aldehyde compound ofFormula-III can be reacted in the presence of alkali or alkaline earthmetal base. The alkali or alkaline earth metal base comprises one ormore of sodium hydroxide, potassium hydroxide, lithium hydroxide,potassium carbonate, sodium carbonate, lithium carbonate, cesiumcarbonate and the like. In particular, it may be potassium carbonate.

Embodiments includes that the reaction can be performed in one or moreof suitable polar aprotic solvent selected from dimethylformamide,dimethylsulfoxide, dimethylacetamide, tetrahydrofuran,N-methylpyrrolidone or mixtures thereof. In particular it may bedimethylsulfoxide at an ambient temperature i.e. at about 15° C. toabout 40° C. In particularly, it may be from about 20° C. to about 35°C.

The reaction mixture can be stirred for about 5 to 15 hours tillcompletion of the reaction. In particular, it may be for 10 hours. Thereaction mixture can be further treated with suitable organic solventslike toluene, xylene, methylene dichloride, ethyl acetate for extractingcompound of Formula-II. In particular, the compound of Formula (II) maybe extracted with toluene.

The compound of Formula-II can be isolated by removal of toluenefollowed by addition of isopropanol. After the addition of isopropanol,the reaction mixture can be heated to 40° C. to 80° C., particularly atabout 60° C. to 70° C. and cooling to 15° C. to obtain compound offormula (II). The compound of formula (II) can be purified in suitablepolar solvent like methanol, ethanol, Isopropanol, acetone, DMF, ethylacetate, butyl acetate and the like. In particular, it may be methanol.

In general, the term “elevated temperature” includes heating thecompound II in a polar solvent at about 50° C. to about 100° C. Inparticular, the compound II may be heated at about 50° C. to about 70°C., most particularly, at about 60° C. to 65° C.

In general, the term “ambient temperature” includes cooling the reactionmixture comprising the compound II in a polar solvent at about 0° C. toabout 30° C. In particular, it may be at about 0° C. to about 15° C.,most particularly, at about 0° C. to 10° C. According to the embodiment,the compound (II) i.e.(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester is obtain in crystalline form afterpurification in polar solvent.

The crystalline form of compound (II) is characterized by an X-raypowder diffraction pattern having characteristics peaks expressed indegrees 2θ (±0.2° 2θ) at 7.86°, 9.94°, 11.48°, 12.71°, 14.80°, 15.88°,17.44°, 18.16°, 19.17°, 19.97°, 20.77°, 22.71°, 23.41°, 24.68°, 26.02°,27.63° and 29.36°±0.2°. The X-ray powder diffraction pattern ischaracterized substantially the same that shown in FIG. 3.

The crystalline form of compound (II) is characterized by an IR spectrumhaving peaks at about 2999, 2976, 1720, 1600, 1512, 1487, 1379, 1342,1288, 1197, 1134, 1066, 1035, 931 and 842 cm⁻¹ and DSC endotherm atabout 116.04° C. The DSC thermogram is substantially the same that shownin FIG. 4.

According to the further embodiment, there is provided a process for thepreparation of pitavastatinzinc of formula (IC),

the process comprising:(a) reacting phosphonium bromide compound of Formula-IV with an aldehydecompound of Formula-III in the presence of an alkali or alkaline earthmetal base in one or more suitable polar aprotic solvent to provide(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester compound of formula-II;(b) hydrolyzing the compound of Formula-II under the acidic conditionsto remove the acetonide protection to form diol compound;(c) treating the diol compound of step (b) in-situ with an alkali metalhydroxide to form the corresponding alkali metal salt of pitavastatin(I);(d) treating the alkali metal salt of pitavastatin (I) with a zincsource to obtain Pitavastatinzinc; and(e) isolating the pitavastatinzinc.

In general, the process parameters for the preparation of compound (II)and its hydrolysis are similar as discloses herein above. The preferablezinc source comprises one or more of zinc formate, zinc acetate, zincpropionate, zinc maleate, zinc fumarate, zinc tartrate, zinc lactate,zinc malate, zinc citrate, Zinc ascorbate, zinc malonate, zinc oxalate,zinc glycolate, zinc methanesulfonate, zinc ethanesulfonate, a salt ofzinc with amino acid, zinc sulfate, zinc chloride, zinc carbonate orzinc nitrate. In particular, it comprises one or more of zinc sulfate,zinc chloride or zinc acetate.

According to the further aspect, there is provided a method for thepreparation of pitavastatinpotassium of formula (ID),

the process comprising:(a) reacting phosphonium bromide compound of Formula-IV with an aldehydecompound of Formula-III in the presence of an alkali or alkaline earthmetal bases in one or more suitable polar aprotic solvent to provide(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester compound of Formula-II,(b) hydrolyzing the compound of Formula-II by subjecting under theacidic conditions to remove the acetonide protection to form diolcompound;(c) treating the diol compound of step (b) in-situ with a potassiumsource to obtain pitavastatinpotassium.

In general, the process parameters for the preparation of compound (II)and its hydrolysis are similar as discloses herein above. The preferablepotassium source comprises one or more of potassium hydroxide, potassiumcarbonate, potassium bicarbonate, potassium acetate, potassium chlorideand the like.

According to the further embodiment, there is provided a process for thepreparation of amorphous form of pitavastatinmagnesium, the processcomprising:

(a) providing a solution comprising pitavastatinmagnesium in a suitableorganic solvent wherein the organic solvent is selected from the groupconsisting of a chlorinated solvent, alcoholic solvent, ketonic solvent,esters solvent and mixtures thereof;

(b) removing the organic solvent to obtain residue;

(c) adding a suitable anti-solvent to the residue; and

(d) recovering the amorphous form of the pitavastatinmagnesium.

The amorphous form can be generally prepared by addition of anti-solventto a concentrated solution of pitavastatinmagnesium in an organicsolvent.

Embodiments of the process includes preparing the solution ofpitavastatinmagnesium in suitable organic solvent selected from thegroup consisting of a chlorinated solvent, alcoholic solvent, ketonicsolvent, ester solvents and mixtures thereof. The preferred solventcomprises one or more of methylene dichloride, ethylene dichloride,chlorobenzene, methanol, ethanol, isopropanol, butanol, acetone,methylethyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, andmixtures thereof or mixture thereof with water. In particular, thesuitable solvent comprises one or more of methanol, acetone, ethylacetate.

In general, the embodiment of the process includes adding suitableantisolvent to the solution of pitavastatinmagnesium in suitable organicsolvent. The suitable anti-solvent comprises one or more of hexane,heptane, cyclohexane, toluene, xylene, diisopropyl ether, methyltert-butyl ether, 1,4-dioxane, tetrahydrofuran and the like. Inparticular, the suitable anti-solvent comprises one or more of heptaneor cyclohexane or methyl tert-butyl ether.

According to the embodiment, there is provided a process for thepreparation of amorphous form of pitavastatinmagnesium, the processcomprising:

(a) providing a solution comprising pitavastatinmagnesium in a suitableorganic solvent wherein the organic solvent is one or more of achlorinated solvent, alcoholic solvent, ketonic solvent, esters solventand mixtures thereof;

(b) heating reaction mixture at an elevated temperature followed bycooling to ambient temperature;

(c) adding a suitable anti-solvent to the solution; and

(d) recovering the amorphous form of pitavastatinmagnesium.

In general, the suitable solvents and anti-solvents comprises from thesame as listed herein above. However, the reaction mixture can be heatedto an elevated temperature in step (b). The elevated temperature is fromabout 50° C. to about 100° C. In particularly, it may be from about 70°C. to about 90° C.

The reaction mixture is then cooled to an ambient temperature,preferably from about 15° C. to about 35° C., preferably from about 25°C. to 35° C.

It is preferable that the anti-solvent and solvent are miscible. Theamorphous form can also be prepared by lyophilization of or removal ofsolvent from the solution of pitavastatinmagnesium in a suitablesolvent.

According to the further embodiments, there is provided a process forthe preparation of amorphous form of pitavastatinmagnesium having watercontent less than about 2% wt/wt, the process comprising:

(a) providing pitavastatinmagnesium in crystalline form having watercontent in the range of about 8% to about 12% wt/wt;

(b) contacting the pitavastatinmagnesium with humid air in a fluidizedbed drier, or maintaining the pitavastatinmagnesium at a temperature offrom about 5 to about 60° C., under pressure of less than 30 mm/Hg for aperiod of from about 1 to 5 days; and

(c) recovering the pitavastatin magnesium in the amorphous form havingwater content less than about 2% wt/wt.

According to the process, amorphous form of pitavastatinmagnesium havingwater content less than about 2% wt/wt is prepared by contactingpitavastatinmagnesium containing about 8% to about 12% of water contentwith humid air in a fluidized bed apparatus.

In particular, the temperature is of about 25° C. to about 50° C., moreparticularly at about 30° C. to about 40° C. The contacting may becarried out, in particularly at about 6 hours to 2 days. As used herein,the term “humid” refers to a relative humidity of at least 30%. Inparticular, it may be at least about 50% and most particularly at leastabout 70%.

According to the further embodiment, there is provided substantiallypure pitavastatinmagnesium in stable crystalline form.

In another embodiment, there is provided pitavastatinmagnesiumsubstantially free desfluoro impurity, cis-isomer impurity, pitavastatin5-oxo impurity, pitavastatinlactone impurity, pitavastatin t-butyl diolester impurity and pitavastatincondensed impurity when measured by areapercentage of HPLC. Also, pitavastatindiastereomeric impurity less than0.3% by area percentage of HPLC.

According to the further embodiment, there is provided a pharmaceuticalcomposition comprising a therapeutically effective amount of crystallinepitavastatinmagnesium characterized by X-ray diffraction pattern havingcharacteristic peaks at 2-theta values 10.1°, 13.2°, 19.3° and27.2°±0.2°, and one or more pharmaceutically acceptable carriers,excipients or diluents.

According to the further embodiment, there is provided a pharmaceuticalcomposition comprising a therapeutically effective amount ofamorphouspitavastatinmagnesium characterized by x-ray diffractionpattern substantially as depicted in FIG. 2, and one or morepharmaceutically acceptable carriers, excipients or diluents.

The starting material, phosphonium bromide compound of Formula-IV, canbe prepared from alcoholic compound of formula (VI)

The alcoholic compound of formula (VI) is converted o phosphoniumcompound of Formula (IV) via formation of3-(bromomethyl)-2-cyclopropyl-4(4′-fluorophenyl)quinoline of Formula (V)by the known process reported in the prior art. WO 95/11898 A1 in itsreference example-7 and Example-1 or as per the process disclosed inU.S. Pat. No. 6,627,636 and U.S. Pat. No. 5,763,675.

The bromo compound of formula (V)3-(bromomethyl)-2-cyclopropyl-4-(4′-fluorophenyl)quinoline with wittigreagent like triphenyl phosphine in suitable non-polar solvents liketoluene, o-xylene, chlorobenzeneetc to obtain phosphonium bromidecompound of formula (IV).

The starting reagent, alcohol compound of formula (VI) can be preparedfrom the known process reported in the art like Tetrahedron Letters,Vol. 34, No. 51, p.p. 8271-8274 (1993); Heterocycles, Vol. 50, No. 1,1999; Drugs of Future 1998 23 (8) or Tetrahedron Asymmetry 1993, Vol. 4,pp. 201-204 are reported herein as reference in its entirety.

As set forth in the following schemes, the pitavastatin magnesium can beprepared by as shown bellow:

The present invention is further illustrated by the following exampleswhich are provided merely to be exemplary of the invention and do notlimit the scope of the invention. Certain modifications and equivalentswill be apparent to those skilled in the art and are intended to beincluded within the scope of the present invention.

Preparation-1 Preparation of3-(bromomethyl)-2-cyclopropyl-4-(4′-fluorophenyl)quinoline (V)

1 Kg of alcohol compound of formula (VI) and 8 L of methylene dichloridewere taken in reactor at 0° C. 0.462 Kg of freshly prepared phosphoniumbromide solution in 2 L methylene dichloride was added slowly andstirred at 25° C. for 2 hours. After the completion of the reaction asmonitored by TLC, the reaction mixture was quenched with 5% sodiumbicarbonate solution to adjust the pH from 7-8. The organic layer wasseparated and washed with 5 L water followed by removal of solvent undervacuum at 45° C. The residue was treated with 2.5 L heptane at 60° C.and cooled to 15° C. The product was filtered at 15° C. and dried undervacuum at 55° C. for 8 hours to obtain3-(bromomethyl)-2-cyclopropyl-4-(4′-fluorophenyl)quinoline.

Preparation-2 Preparation of Phosphonium Bromide Compound of Formula(IV)

1 Kg of 3-(bromomethyl)-2-cyclopropyl-4-(4′-fluorophenyl)quinoline, 10 Lof toluene and 300 mL of isopropanol were taken in reactor and heated at50° C. 0.874 Kg of triphenyl phosphine solution in 2 L toluene was addedslowly and stirred for 3 hours. The reaction mixture was cooled to 25°C. and stirred for 1 hour. The product was filtered and washed withtoluene. The product was dried in tray dryer at 55° C. for 8 hours toobtain phosphonium bromide compound of formula (IV).

Example-1 Preparation of(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester Compound of Formula II

To the solution of 0.751 Kg oftert-butyl-2-((4R,6S)-6-formula-2,2-dimethyl-1,3-dioxan-4-yl)acetate(III) in 7 L of dimethylsulphoxide was added 1 Kg of phosphonium bromidecompound of formula (IV) and 0.67 Kg of potassium carbonate. Thereaction mixture was stirred at 25° C. for 10 hours. The reactionmixture was quenched with water and extracted with toluene. The organiclayer was concentrated and the title compound was isolated usingisopropanol as crude solid. The crude product thus obtained wasrecrystallized in methanol as shown below.

Purification of Olefin Compound of Formula II

Pitavastatin Olefin compound (II) (100 g) and methanol (600 mL) wereheated to 60° C. to 65° C. to obtain the clear solution and stirred for10 mins. Activated Carbon (10 g) were added at 60° C. to 65° C. andstirred for 10 min. The reaction mixture was filtered and washed withmethanol (100 mL). The filtrate was cooled to 25° C. and gradually to10° C. followed by stirring for 2 hours at 10° C. The resulting slurrywas filtered and washed with chilled methanol (100 mL). The wet-cake washeated in methanol (480 mL) at 60° C. to 65° C. to obtain the clearsolution. Activated Carbon (10 g) were added at 60° C. to 65° C. andstirred for 10 min. The reaction mixture was filtered and washed withmethanol (100 mL). The filtrate was cooled to 25° C. and gradually to10° C. followed by stirring for 2 hours at 10° C. The resulting slurrywas filtered and washed with chilled methanol (100 mL). The wet-cake wasdried under vacuum for 30 minutes followed by drying in hot air oven at50° C. to 55° C. for 12 hours to obtain crystalline olefin compound (II)characterized by X-ray powder diffraction substantially as same as shownin FIG. 3 and DSC thermogram having endothermic peak at about 116.04° C.as shown in FIG. 4.

Example-2 Preparation of Pitavastatin Magnesium of Formula (IB)

To the solution of 100 g of(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester compound of formula II (crystalline) in 1 Lmethanol was added 272.8 mL 1N HCl solution at 25° C. The reactionmixture was stirred for 8 hours. The reaction mixture was cooled to 15°C. and treated with 23.2 g 10% sodium hydroxide solution.

The reaction mixture was stirred for 4 hours at 25° C. and quenched inwater. The reaction mass was treated with 92 mL 1 N HCl solution toadjust the pH of about 8.0 and treated with methylene dichloride forwashing. The separated aqueous layer is treated with 100 g of magnesiumchloride hexahydrate and stirred for 30 min at 25° C. The solution iscooled to 15° C., filtered and washed with water. The product is driedin hot air oven for 4 hours to obtain 82 g of crystalline PitavastatinMagnesium having water content of 11.0%. (XRD as shown in FIG. 1)

Example-3 Preparation of Pitavastatin Zinc of Formula (IC)

To the solution of 100 g of(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester compound of formula II (crystalline) in 1 Lmethanol was added 272.8 mL 1N HCl solution at 25° C. The reactionmixture was stirred for 8 hours. The reaction mixture was cooled to 15°C. and treated with 23.2 g 10% sodium hydroxide solution. The reactionmixture was stirred for 4 hours at 25° C. and quenched in water. Thereaction mass was treated with 92 mL 1 N HCl solution to adjust the pHof about 8.0 and treated with methylene dichloride for washing. Theseparated aqueous layer is treated with 100 g of zinc sulfate andstirred for 30 min at 25° C. The solution is cooled to 15° C., filteredand washed with water. The product is dried in hot air oven for 4 hoursto obtain 75 g of crystalline Pitavastatin zinc.

Example-4 Preparation of Pitavastatin Potassium of Formula (ID)

To the solution of 100 g of(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester compound of formula II (crystalline) in 1 Lmethanol was added 272.8 mL 1N HCl solution at 25° C. The reactionmixture was stirred for 8 hours. The reaction mixture was cooled to 15°C. and treated with 23.2 g 10% sodium hydroxide solution. The reactionmixture was stirred for 4 hours at 25° C. and quenched in water. Thereaction mass was treated with 92 mL 1 N HCl solution to adjust the pHof about 8.0 and treated with methylene dichloride for washing. Theseparated aqueous layer is treated with 80 g of Potassium hydroxide andstirred for 30 min at 25° C. The solution is cooled to 15° C., filteredand washed with water. The product is dried in hot air oven for 4 hoursto obtain 72 g of crystalline Pitavastatin Potassium.

Example 5 Preparation of the Amorphous Form of Pitavastatin Magnesium

100 g of crystalline Pitavastatin Magnesium was dissolved in 800 mlEthyl Acetate by heating at 75° C. to 80° C. The slightly turbidsolution was filtered through hyflow bed at 75° C. to 80° C. Thefiltrate was cooled to 25° C. and added to cyclohexane (3300 mL). Thereaction mixture was stirred for 2 hours. The reaction mixture wasfiltered and wet-cake was washed with cyclohexane (100 mL). The productwas dried in hot air oven for 12 hours to get 83.0 g amorphousPitavastatin Magnesium. The obtained solid was amorphous as is shown bythe X-ray diffraction pattern given in FIG. 2.

Example 6 Preparation of the Amorphous Form of Pitavastatin Magnesium

100 g of crystalline Pitavastatin Magnesium was dissolved in 800 mlEthyl Acetate by heating at 75° C. to 80° C. The slightly turbidsolution was filtered through hyflow bed at 75° C. to 80° C. Thefiltrate was distilled under vacuum till dry powder obtained at 45° C.to 50° C. The solid was cooled to 25° C. and cyclohexane (500 mL) wasadded to the filtrate and stirred for 30 min. The reaction mixture wasfiltered and wet-cake was washed with cyclohexane (100 mL). The productwas dried in hot air oven for 12 hours to get 83.0 g amorphousPitavastatin Magnesium. The obtained solid was amorphous as is shown bythe X-ray diffraction pattern given in FIG. 2.

Example 7 Preparation of the Amorphous Form of Pitavastatin Magnesium

100 g of crystalline Pitavastatin Magnesium and Methanol (500 mL) werestirred in RBF for 30 minutes. The reaction mixture was distilled at 45°C. to 50° C. under vacuum to obtain dry product. The filtrate wasdistilled under vacuum till dry powder obtained at 45° C. to 50° C. Thesolid was cooled to 25° C. and cyclohexane (500 mL) was added to thefiltrate and stirred for 30 min. The reaction mixture was filtered andwet-cake was washed with cyclohexane (100 mL). The product was dried inhot air oven for 12 hours to get 83.0 g amorphous PitavastatinMagnesium.

Example 8 Preparation of the Amorphous Form of Pitavastatin Magnesium

100 g of crystalline Pitavastatin Magnesium was dissolved in 800 mlAcetone by heating at 55° C. to 60° C. The slightly turbid solution wasfiltered through hyflow bed at 55° C. to 60° C. The filtrate was cooledto 25° C. and added to diisopropyl ether (3000 mL). The reaction mixturewas stirred for 3-min. The reaction mixture was filtered and wet-cakewas washed with diisopropyl ether (100 mL). The product was dried in hotair oven for 12 hours to get 45.0 g amorphous Pitavastatin Magnesium.

Example 9 Preparation of the Amorphous Form of Pitavastatin Magnesium

100 g of Pitavastatin Magnesium having water content 11% was dried influid bed dried at 45° C. for 2 days to obtain amorphous PitavastatinMagnesium having water content less than 2% wt/wt. An X-ray diffractionstudy on the product showed it to be amorphous.

Example 10 Preparation of the Amorphous Form of Pitavastatin Magnesium

100 g of Pitavastatin Magnesium having water content 11% was dried invacuum tray dryer at about 5 to about 60° C., under pressure of lessthan 30 mm/Hg for a period of 24 hours to obtain amorphous PitavastatinMagnesium having water content less than 2% wt/wt. An X-ray diffractionstudy on the product showed it to be amorphous, see FIG. 2.

While the present invention has been described in terms of its specificembodiments, certainmodifications and equivalents will be apparent tothose skilled in the art and are intended to be included within thescope of the present invention.

Advantages of the Invention

1. The present invention provides novel pharmaceutically acceptable saltof alkali metal salts of Pitavastatin.

2. The present invention provides an improved process for thepreparation of pitavastatinalkali metal salts.

3. The present invention provides crystalline form ofpitavastatinmagnesium having 8% to 12% water content.

4. The present invention also provides amorphous form ofpitavastatinmagnesium and process for preparation thereof.

5. The present invention provides amorphous form ofpitavastatinmagnesium containing less than about 2% of water content.

6. The process provided is eco-friendly, economically viable and easilyscalable on large scale production.

We claim:
 1. An isolated pitavastatin magnesium compound of Formula (IB)or a hydrate thereof


2. The compound as claimed in claim 1, wherein the compound has a watercontent in the range of from about 7% to about 12% wt/wt.
 3. Acrystalline pitavastatin magnesium compound of Formula (IB) or a hydratethereof

wherein the crystalline pitavastatin magnesium compound has an X-raypowder diffraction pattern having characteristic peaks expressed indegrees 2θ (±0.2° 2θ) at 10.1°, 13.2°, 19.3° and 27.2°±0.2°.
 4. Thecompound as claimed in claim 3 having an x-ray powder diffractionpattern substantially same as that shown in FIG.
 1. 5. The compound asclaimed in claim 2, wherein the compound is amorphous.
 6. An amorphouspitavastatin magnesium compound of Formula (IB) or a hydrate thereofhaving an x-ray powder diffraction pattern substantially the same asthat shown in FIG. 2


7. The compound as claimed in claim 5, wherein the compound has a watercontent less than about 5% wt/wt.
 8. The compound as claimed in claim 5having a specific optical rotation of about +22.0 to +22.5 in 1% DMSO at20±0.5° C.
 9. A pharmaceutical composition comprising pitavastatinmagnesium of claim 5 and one or more pharmaceutically acceptablecarriers or excipients.
 10. The compound as claimed in claim 5, whereinthe pitavastatin magnesium is substantially pure having purity greaterthan about 99% by area percentage of HPLC.
 11. The compound as claimedin claim 5, wherein the pitavastatin magnesium is substantially purehaving less than about 0.3% of diastereomeric impurity by areapercentage of HPLC.
 12. A process for the preparation of pitavastatinmagnesium of Formula (IB) as claimed in claim 5,

the process comprising: (a) reacting phosphonium bromide compound ofFormula-IV

with an aldehyde compound of Formula-III

in the presence of an alkali or alkaline earth metal base in one or moresuitable polar aprotic solvents to provide(4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]aceticacid tertiary butyl ester compound of Formula-II;

(b) hydrolyzing the compound of Formula-II under acidic conditions toremove acetonide protection to form a diol compound; (c) treating thediol compound of step (b) in situ with an alkali metal hydroxide to formcorresponding alkali metal salt of pitavastatin (I);

wherein, M is Na⁺, K⁺, Li⁺; (d) treating alkali metal salt ofpitavastatin (I) with a magnesium source to obtain pitavastatinmagnesium; and (e) isolating the pitavastatin magnesium.
 13. The processas claimed in claim 12, wherein in step (a) the alkali or alkaline earthmetal base comprises one or more of sodium hydroxide, potassiumhydroxide, lithium hydroxide, potassium carbonate, sodium carbonate,lithium carbonate, and cesium carbonate.
 14. The process as claimed inclaim 12, wherein in step (a) the suitable polar aprotic solventcomprises one or more of dimethylformamide, dimethylsulfoxide,dimethylacetamide, tetrahydrofuran, N-methylpyrrolidone, or mixturesthereof.
 15. The process as claimed in claim 12, wherein the compound(II) can optionally be isolated by removal of the solvent.
 16. Theprocess as claimed in claim 12, wherein the compound (II) can optionallybe purified in a suitable polar solvent selected from methanol, ethanol,isopropanol, acetone, DMF, ethyl acetate, or butyl acetate.
 17. Theprocess as claimed in claim 12, wherein in step (b) the hydrolysis ofcompound (II) under acidic conditions can be done by selecting suitableacids from hydrochloric acid, acetic acid, sulfuric acid, nitric acid,and phosphoric acid.
 18. The process as claimed in claim 12, wherein instep (c) the alkali metal hydroxide comprises one or more of sodiumhydroxide, potassium hydroxide, and lithium hydroxide.
 19. The processas claimed in claim 15, wherein in step (c) the alkali metal salt ofpitavastatin is pitavastatin sodium.
 20. The process as claimed in claim12, wherein in step (d) the magnesium source comprises one or more ofmagnesium chloride, magnesium methoxide, magnesium acetate and hydratesthereof.
 21. The process as claimed in claim 15, wherein in step (e) thepitavastatin magnesium is isolated in a crystalline form.
 22. Acrystalline pitavastatin magnesium compound of Formula (IB) or a hydratethereof,

wherein the pitavastatin magnesium compound has an X-ray powderdiffraction pattern having characteristics peaks expressed in degrees 2θ(±0.2° 20) at 10.1°, 13.2°, 19.3° and 27.2°±0.2° and is characterized byone or more of: (a) having a specific optical rotation of about +22.0 to+22.5 in 1% DMSO at 20±0.5° C.; (b) having a purity greater than about99% by area percentage of HPLC; and (c) having less than about 0.3% ofdiastereomeric impurity by area percentage of HPLC.
 23. A pitavastatinmagnesium compound of Formula (IB) or a hydrate thereof,

wherein the pitavastatin magnesium compound is crystalline and has anX-ray powder diffraction pattern having characteristics peaks expressedin degrees 2θ (±0.2° 20) at 10.1°, 13.2°, 19.3° and 27.2°±0.2°; or thepitavastatin magnesium compound is crystalline and has an x-ray powderdiffraction pattern substantially same as that shown in FIG. 1; or thepitavastatin magnesium compound is amorphous and has an x-ray powderdiffraction pattern substantially the same as that shown in FIG.
 2. 24.The compound as claimed in claim 23, wherein the compound is crystallineand has a water content in the range of from about 7% to about 12%wt/wt.
 25. The compound as claimed in claim 23, wherein the compound isamorphous and has a water content less than about 5% wt/wt.
 26. Thecompound as claimed in claim 23, having a specific optical rotation ofabout +22.0 to +22.5 in 1% DMSO at 20±0.5° C.
 27. The compound asclaimed in claim 23, wherein the pitavastatin magnesium is substantiallypure having a purity greater than about 99% by area percentage of HPLC.28. The compound as claimed in claim 23, wherein the pitavastatinmagnesium is substantially pure having less than about 0.3% ofdiastereomeric impurity by area percentage of HPLC.
 29. A pharmaceuticalcomposition comprising the pitavastatin magnesium of claim 23 and one ormore pharmaceutically acceptable carriers or excipients.
 30. Thecompound as claimed in claim 6, wherein the amorphous pitavastatinmagnesium compound has a water content less than about 5% wt/wt.